Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein

Détails

ID Serval
serval:BIB_6058765DDE09
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein
Périodique
British journal of clinical pharmacology
Auteur(s)
Widmer N., Decosterd L.A., Csajka C., Leyvraz S., Duchosal M.A., Rosselet A., Rochat B., Eap C.B., Henry H., Biollaz J., Buclin T.
ISSN
0306-5251
Statut éditorial
Publié
Date de publication
2006
Peer-reviewed
Oui
Volume
62
Numéro
1
Pages
97-112
Langue
anglais
Notes
Publication types: Journal Article - Publication Status: ppublish
Résumé
AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. RESULTS: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. CONCLUSION: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.
Mots-clé
Administration, Oral, Adult, Age Factors, Aged, Antineoplastic Agents, Body Weight, Female, Gastrointestinal Stromal Tumors, Humans, Intestinal Absorption, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Orosomucoid, Piperazines, Pyrimidines, Sex Factors
Pubmed
Web of science
Open Access
Oui
Création de la notice
05/02/2008 13:39
Dernière modification de la notice
20/08/2019 14:17
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